STAT3 mRNA and protein expression in colorectal cancer:: effects on STAT3-inducible targets linked to cell survival and proliferation

Aims: To evaluate mRNA and protein expression of signal transducers and activators of transcription (STAT) 3 in colorectal carcinomas (CRCs) and to define the association of STAT3 activity with the STAT3-inducible targets cyclin D1, survivin, Bcl-xl and Mcl-1. Materials and methods: Matching serial sections of normal colonic epithelium and invasive CRCs (n = 32) were subjected to quantitative reverse transcriptase polymerase chain reaction specific to STAT3, cyclin D1, survivin, Bcl-xl and Mcl-1, as well as immunohistochemistry. For STAT3 immunohistochemistry, two antibodies, recognising unphosphorylated (UP-) and phosphorylated (tyr705, P-) STAT3 were used. Ki-67 (MIB-1) staining was included as a proliferation marker. Results: Compared with normal colonic epithelium, UP-STAT3 and P-STAT3 (p = 0.023 and 0.006) protein expression and expression of its associated targets cyclin D1, survivin and Bcl-xl were significantly (all p < 0.001) increased in carcinoma. In carcinomas, STAT3 (p = 0.019) and Bcl-xl (p = 0.001) mRNAs were correlated with lymph node status. Moreover, nuclear P-STAT3 protein expression (active state) was associated with the expression of its target genes Bcl-xl (p = 0.038) and survivin (p = 0.01) as well as with Ki-67 (p = 0.017). By contrast, cytoplasmic UP- STAT was significantly linked to Bcl-xl mRNA (p = 0.024) and protein (p = 0.001) as well as to cytoplasmic survivin protein expression (p = 0.019). Conclusion: Both inactive (UP- STAT3) and active (P-STAT3) STAT3 proteins are markedly increased in invasive CRCs. This is associated with Bcl-xl and survivin induction, increased proliferation and lymph node metastasis. This study therefore provides the basis for further examination of the prognostic or predictive value of these molecular markers in CRC.